Effect of inpatient and outpatient care on treatment outcome in tuberculosis: a cohort study.

OBJECTIVE: To identify individual- and health services-related factors associated with deaths in subjects diagnosed with tuberculosis (TB). METHODS: A nonconcurrent cohort study with passive follow-up was conducted using a probabilistic linkage method to analyze a sample of patients diagnosed and reported as having TB in 2006 and followed up until 2008. New cases, cases with previous treatment (readmission after loss to follow-up or relapse), and transfers across health services were included. Proportional hazards models were used to estimate the independent effect of covariates related to the individual and to the health services on mortality from all causes. RESULTS: Age above 60 years, admission to a hospital with emergency services, HIV-associated TB, and readmission to an outpatient facility after disease relapse or loss to follow-up were identified as risk factors for death. Variables related to process and results indicators of Brazil's National TB Program were not associated with mortality from all causes. CONCLUSIONS: Advanced age, previous treatment for TB, and treatment at a secondary-level outpatient facility or a hospital with emergency services on site were associated with mortality in TB patients. Better strategies to improve TB care delivered at health units are needed to prevent death from TB, especially among the elderly.

The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology.

BACKGROUND/AIMS: Evidence suggests that tyrosine-kinase inhibitors may attenuate lung inflammation and fibrosis in experimental acute respiratory distress syndrome (ARDS). We hypothesized that dasatinib, a tyrosine-kinase inhibitor, might act differently depending on the ARDS etiology and the dose. METHODS: C57/BL6 mice were divided to be pre-treated with dasatinib (1mg/kg or 10mg/kg) or vehicle (1% dimethyl-sulfoxide) by oral gavage. Thirty-minutes after pre-treatment, mice were subdivided into control (C) or ARDS groups. ARDS animals received Escherichia coli lipopolysaccharide intratracheally (ARDSp) or intraperitoneally (ARDSexp). A new dose of dasatinib or vehicle was administered at 6 and 24h. RESULTS: Forty-eight hours after ARDS induction, dasatinib 1mg/kg yielded: improved lung morphofunction and reduced cells expressing toll-like receptor (TLR)-4 in lung, independent of ARDS etiology; reduced neutrophil and levels of interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-ß in ARDSp. The higher dose of dasatinib caused no changes in lung mechanics, diffuse alveolar damage, neutrophil, or cells expressing TLR4, but increased IL-6, vascular endothelial growth factor (VEGF), and cells expressing Fas receptor in lung in ARDSp. In ARDSexp, it improved lung morphofunction, increased VEGF, and reduced cells expressing TLR4. Conclusion: Dasatinib may have therapeutic potential in ARDS independent of etiology, but careful dose monitoring is required.

Pivotal role of the 5-lipoxygenase pathway in lung injury after experimental sepsis.

Postsepsis lung injury is a common clinical problem associated with significant morbidity and mortality. Leukotrienes (LTs) are important lipid mediators of infection and inflammation derived from the 5-lipoxygenase (5-LO) metabolism of arachidonate with the potential to contribute to lung damage after sepsis. To test the hypothesis that LTs are mediators of lung injury after sepsis, we assessed lung structure, inflammatory mediators, and mechanical changes after cecal ligation and puncture surgery in wild-type (WT) and 5-LO knockout (5-LO(-/-)) mice and in WT mice treated with a pharmacologic LT synthesis inhibitor (MK886) and LT receptor antagonists (CP105,696 and montelukast). Sixteen hours after surgery, WT animals exhibited severe lung injury (by histological analysis), substantial mechanical impairment (i.e., an increase in static lung elastance), an increase in neutrophil infiltration, and high levels of LTB4, cysteinyl-LTs (cys-LTs), prostaglandin E2, IL-1ß, IL-6, IL-10, IL-17, KC (CXCL1), and monocyte chemotactic protein-1 (CCL2) in lung tissue and plasma. 5-LO(-/-) mice and WT mice treated with a pharmacologic 5-LO inhibitor were significantly protected from lung inflammation and injury. Selective antagonists for BLT1 or cys-LT1, the high-affinity receptors for LTB4 and cys-LTs, respectively, were insufficient to provide protection when used alone. These results point to an important role for 5-LO products in sepsis-induced lung injury and suggest that the use of 5-LO inhibitors may be of therapeutic benefit clinically.

Hypervolemia induces and potentiates lung damage after recruitment maneuver in a model of sepsis-induced acute lung injury.

INTRODUCTION: Recruitment maneuvers (RMs) seem to be more effective in extrapulmonary acute lung injury (ALI), caused mainly by sepsis, than in pulmonary ALI. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. Since the interaction between volemic status and RMs is not well established, we investigated the effects of RMs on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervolemia in a model of extrapulmonary lung injury induced by sepsis. METHODS: ALI was induced by cecal ligation and puncture surgery in 66 Wistar rats. After 48 h, animals were anesthetized, mechanically ventilated and randomly assigned to 3 volemic status (n = 22/group): 1) hypovolemia induced by blood drainage at mean arterial pressure (MAP) approximately 70 mmHg; 2) normovolemia (MAP approximately 100 mmHg), and 3) hypervolemia with colloid administration to achieve a MAP approximately 130 mmHg. In each group, animals were further randomized to be recruited (CPAP = 40 cm H2O for 40 s) or not (NR) (n = 11/group), followed by 1 h of protective mechanical ventilation. Echocardiography, arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, interleukin (IL)-6, IL-1beta, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis were analyzed. RESULTS: We observed that: 1) hypervolemia increased lung W/D ratio with impairment of oxygenation and Est,L, and was associated with alveolar and endothelial cell damage and increased IL-6, VCAM-1, and ICAM-1 mRNA expressions; and 2) RM reduced alveolar collapse independent of volemic status. In hypervolemic animals, RM improved oxygenation above the levels observed with the use of positive-end expiratory pressure (PEEP), but increased lung injury and led to higher inflammatory and fibrogenetic responses. CONCLUSIONS: Volemic status should be taken into account during RMs, since in this sepsis-induced ALI model hypervolemia promoted and potentiated lung injury compared to hypo- and normovolemia.

Understanding the mechanisms of glutamine action in critically ill patients.

Glutamine (Gln) is an important energy source and has been used as a supplementary energy substrate. Furthermore, Gln is an essential component for numerous metabolic functions, including acid-base homeostasis, gluconeogenesis, nitrogen transport and synthesis of proteins and nucleic acids. Therefore, glutamine plays a significant role in cell homeostasis and organ metabolism. This article aims to review the mechanisms of glutamine action during severe illnesses. In critically ill patients, the increase in mortality was associated with a decreased plasma Gln concentration. During catabolic stress, Gln consumption rate exceeds the supply, and both plasma and skeletal muscle pools of free Gln are severely reduced. The dose and route of Gln administration clearly influence its effectiveness: high-dose parenteral appears to be more beneficial than low-dose enteral administration. Experimental studies reported that Gln may protect cells, tissues, and whole organisms from stress and injury through the following mechanisms: attenuation of NF (nuclear factor)-kB activation, a balance between pro- and anti-inflammatory cytokines, reduction in neutrophil accumulation, improvement in intestinal integrity and immune cell function, and enhanced of heat shock protein expression. In conclusion, high-doses of parenteral Gln (>0.50 g/kg/day) demonstrate a greater potential to benefit in critically ill patients, although Gln pathophysiological mechanisms requires elucidation.

Nanoparticle-based thymulin gene therapy therapeutically reverses key pathology of experimental allergic asthma.

Despite long-standing efforts to enhance care for chronic asthma, symptomatic treatments remain the only option to manage this highly prevalent and debilitating disease. We demonstrate that key pathology of allergic asthma can be almost completely resolved in a therapeutic manner by inhaled gene therapy. After the disease was fully and stably established, we treated mice intratracheally with a single dose of thymulin-expressing plasmids delivered via nanoparticles engineered to have a unique ability to penetrate the airway mucus barrier. Twenty days after the treatment, we found that all key pathologic features found in the asthmatic lung, including chronic inflammation, pulmonary fibrosis, and mechanical dysregulation, were normalized. We conducted tissue- and cell-based analyses to confirm that the therapeutic intervention was mediated comprehensively by anti-inflammatory and antifibrotic effects of the therapy. We believe that our findings open a new avenue for clinical development of therapeutically effective gene therapy for chronic asthma.

Intravenous glutamine decreases lung and distal organ injury in an experimental model of abdominal sepsis.

INTRODUCTION: The protective effect of glutamine, as a pharmacological agent against lung injury, has been reported in experimental sepsis; however, its efficacy at improving oxygenation and lung mechanics, attenuating diaphragm and distal organ injury has to be better elucidated. In the present study, we tested the hypothesis that a single early intravenous dose of glutamine was associated not only with the improvement of lung morpho-function, but also the reduction of the inflammatory process and epithelial cell apoptosis in kidney, liver, and intestine villi. METHODS: Seventy-two Wistar rats were randomly assigned into four groups. Sepsis was induced by cecal ligation and puncture surgery (CLP), while a sham operated group was used as control (C). One hour after surgery, C and CLP groups were further randomized into subgroups receiving intravenous saline (1 ml, SAL) or glutamine (0.75 g/kg, Gln). At 48 hours, animals were anesthetized, and the following parameters were measured: arterial oxygenation, pulmonary mechanics, and diaphragm, lung, kidney, liver, and small intestine villi histology. At 18 and 48 hours, Cytokine-Induced Neutrophil Chemoattractant (CINC)-1, interleukin (IL)-6 and 10 were quantified in bronchoalveolar and peritoneal lavage fluids (BALF and PLF, respectively). RESULTS: CLP induced: a) deterioration of lung mechanics and gas exchange; b) ultrastructural changes of lung parenchyma and diaphragm; and c) lung and distal organ epithelial cell apoptosis. Glutamine improved survival rate, oxygenation and lung mechanics, minimized pulmonary and diaphragmatic changes, attenuating lung and distal organ epithelial cell apoptosis. Glutamine increased IL-10 in peritoneal lavage fluid at 18 hours and bronchoalveolar lavage fluid at 48 hours, but decreased CINC-1 and IL-6 in BALF and PLF only at 18 hours. CONCLUSIONS: In an experimental model of abdominal sepsis, a single intravenous dose of glutamine administered after sepsis induction may modulate the inflammatory process reducing not only the risk of lung injury, but also distal organ impairment. These results suggest that intravenous glutamine may be a potentially beneficial therapy for abdominal sepsis.

Mesenchymal Stromal Cells Are More Effective Than Their Extracellular Vesicles at Reducing Lung Injury Regardless of Acute Respiratory Distress Syndrome Etiology.

Although mesenchymal stromal cells (MSCs) have demonstrated beneficial effects on experimental acute respiratory distress syndrome (ARDS), preconditioning may be required to potentiate their therapeutic effects. Additionally, administration of cell-free products, such as extracellular vesicles (EVs) obtained from MSC-conditioned media, might be as effective as MSCs. In this study, we comparatively evaluated the effects of MSCs, preconditioned or not with serum collected from mice with pulmonary or extrapulmonary ARDS (ARDSp and ARDSexp, respectively), and the EVs derived from these cells on lung inflammation and remodeling in ARDSp and ARDSexp mice. Administration of MSCs (preconditioned or not), but not their EVs, reduced static lung elastance, interstitial edema, and collagen fiber content in both ARDSp and ARDSexp. Although MSCs and EVs reduced alveolar collapse and neutrophil cell counts in lung tissue, therapeutic responses were superior in mice receiving MSCs, regardless of preconditioning. Despite higher total cell, macrophage, and neutrophil counts in bronchoalveolar lavage fluid in ARDSp than ARDSexp, MSCs and EVs (preconditioned or not) led to a similar decrease. In ARDSp, both MSCs and EVs, regardless of preconditioning, reduced levels of tumor necrosis factor- (TNF-) α, interleukin-6, keratinocyte chemoattractant (KC), vascular endothelial growth factor (VEGF), and transforming growth factor- (TGF-) ß in lung homogenates. In ARDSexp, TNF-α, interleukin-6, and KC levels were reduced by MSCs and EVs, preconditioned or not; only MSCs reduced VEGF levels, while TGF-ß levels were similarly increased in ARDSexp treated either with saline, MSCs, or EVs, regardless of preconditioning. In conclusion, MSCs yielded greater overall improvement in ARDS in comparison to EVs derived from the same number of cells and regardless of the preconditioning status. However, the effects of MSCs and EVs differed according to ARDS etiology.

Exogenous Glutamine in Respiratory Diseases: Myth or Reality?

Several respiratory diseases feature increased inflammatory response and catabolic activity, which are associated with glutamine depletion; thus, the benefits of exogenous glutamine administration have been evaluated in clinical trials and models of different respiratory diseases. Recent reviews and meta-analyses have focused on the effects and mechanisms of action of glutamine in a general population of critical care patients or in different models of injury. However, little information is available about the role of glutamine in respiratory diseases. The aim of the present review is to discuss the evidence of glutamine depletion in cystic fibrosis (CF), asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and lung cancer, as well as the results of exogenous glutamine administration in experimental and clinical studies. Exogenous glutamine administration might be beneficial in ARDS, asthma, and during lung cancer treatment, thus representing a potential therapeutic tool in these conditions. Further experimental and large randomized clinical trials focusing on the development and progression of respiratory diseases are necessary to elucidate the effects and possible therapeutic role of glutamine in this setting.

Effects of early and late pneumothorax drainage on the development of pulmonary oedema.

We analyzed the effects of pneumothorax duration and early or late drainage on lung histology and biological markers associated with inflammation, alveolar fluid clearance, and pulmonary oedema formation. Pneumothorax was induced by injecting air into the thorax of anaesthetized rats, which were randomized according to duration of pneumothorax [5 (PTX5) or 30 (PTX30)min] and further divided to be drained (D) or not (ND). ND rats were euthanized at 5 and 30min. In D groups, pneumothorax was drained and rats breathed spontaneously for 30min. PTX30-ND, compared to PTX5-ND, showed higher alveolar collapse and oedema, type III procollagen, caspase-3, epithelial sodium channel-α, and aquaporin (AQP)-1 mRNA expression, and epithelial and endothelial damage, with reduced cystic fibrosis transmembrane conductance regulator (CFTR) and AQP-3 expression. PTX5-D, compared to PTX30-D, showed less alveolar hyperinflation, oedema, and alveolar-capillary damage, with reduced interleukin-6, caspase-3, AQP-5, and Na,K-ATPase-α and -ß expression, and increased CFTR expression. In conclusion, longer duration pneumothorax exacerbated lung damage, oedema, and inflammation.

Effect of inpatient and outpatient care on treatment outcome in tuberculosis: a cohort study

[ABSTRACT]. Objective. To identify individual- and health services–related factors associated with deaths in subjects diagnosed with tuberculosis (TB). Methods. A nonconcurrent cohort study with passive follow-up was conducted using a probabilistic linkage method to analyze a sample of patients diagnosed and reported as having TB in 2006 and followed up until 2008. New cases, cases with previous treatment (readmission after loss to follow-up or relapse), and transfers across health services were included. Proportional hazards models were used to estimate the independent effect of covariates related to the individual and to the health services on mortality from all causes. Results. Age above 60 years, admission to a hospital with emergency services, HIV-associated TB, and readmission to an outpatient facility after disease relapse or loss to follow-up were identified as risk factors for death. Variables related to process and results indicators of Brazil’s National TB Program were not associated with mortality from all causes. Conclusions. Advanced age, previous treatment for TB, and treatment at a secondary-level outpatient facility or a hospital with emergency services on site were associated with mortality in TB patients. Better strategies to improve TB care delivered at health units are needed to prevent death from TB, especially among the elderly.

[RESUMEN]. Objetivo. Identificar los factores individuales y los factores relacionados con los servicios de salud asociados con la muerte de personas con diagnóstico de tuberculosis. Métodos. Se realizó un estudio de cohortes no concurrentes con seguimiento pasivo, con un método de nexo probabilístico, para analizar una muestra de pacientes a quienes se les diagnosticó tuberculosis y se notificaron sus casos en el 2006, y se les dio seguimiento hasta el 2008. Se incluyeron casos nuevos, casos con tratamiento anterior (reingreso después de haber abandonado el seguimiento o por recaída) y transferencias entre distintos servicios de salud. Se usaron modelos de riesgos proporcionales para calcular el efecto independiente de las covariables relacionadas con los individuos y con los servicios de salud en la mortalidad por todas las causas. Resultados. Se determinó que los factores de riesgo de muerte son: edad mayor de 60 años, ingreso a un hospital con servicios de urgencia, tuberculosis asociada con la infección por el VIH y reingreso a un establecimiento de atención ambulatoria después de la recaída de la enfermedad o de abandonar el seguimiento. Las variables relacionadas con los procesos y los indicadores de resultados del Programa Nacional contra la Tuberculosis de Brasil no se asociaron con la mortalidad por todas las causas. Conclusiones. La edad avanzada, el antecedente de tratamiento antituberculoso y el tratamiento en un establecimiento ambulatorio de nivel secundario o un hospital con servicios integrados de urgencia se asociaron con la mortalidad de los pacientes con tuberculosis. Se necesitan mejores estrategias para optimizar los servicios de atención de la tuberculosis que prestan las unidades de salud a fin de evitar la muerte por esta enfermedad, especialmente en las personas de mayor edad.

[RESUMO]. Objetivo. Identificar fatores individuais e relacionados aos serviços de saúde asociados com mortalidade em indivíduos com diagnóstico de tuberculose (TB). Métodos. Estudo longitudinal não concorrente de seguimento passivo por método de linkage probabilístico, realizado em uma amostra de pacientes diagnosticados e notificados com TB em 2006 e seguidos até 2008. Casos novos, com histórico de tratamento anterior (readmitidos após perda de seguimento ou recorrência) ou transmitidos entre diferentes serviços de saúde foram incluídos. Modelos de riscos proporcionais foram utilizados para estimar o efeito independente de covariáveis do individuo e do serviço de saúde na mortalidade por todas as causas. Resultados. Idade maior de 60 anos, admissão em hospital com serviço de emergência, coinfecção HIV/TB e reingresso a um serviço ambulatorial após recorrência da TB ou perda de seguimento foram identificados como fatores de risco para a morte. Variáveis de processo e indicadores de resultados do Programa Nacional de Controle da Tuberculose não guardaram relação com a mortalidade por todas as causas. Conclusões. Idade avançada, tratamento prévio da TB e tratamento em unidade ambulatorial de nível secundário ou em hospital com serviço de emergência no local apresentaram associação com mortalidade em pacientes com TB. São necessárias estratégias melhores para aprimorar a atenção à TB ofertada nas unidades de saúde, principalmente para idosos.

Effect of inpatient and outpatient care on treatment outcome in tuberculosis: a cohort study / Efecto de la atención hospitalaria y ambulatoria en el resultado del tratamiento de la tuberculosis: un estudio de cohortes / Efeito da atenção hospitalar e ambulatorial sobre o desfecho do tratamento da tuberculose: estudo de coorte

ABSTRACT Objective To identify individual- and health services-related factors associated with deaths in subjects diagnosed with tuberculosis (TB). Methods A nonconcurrent cohort study with passive follow-up was conducted using a probabilistic linkage method to analyze a sample of patients diagnosed and reported as having TB in 2006 and followed up until 2008. New cases, cases with previous treatment (readmission after loss to follow-up or relapse), and transfers across health services were included. Proportional hazards models were used to estimate the independent effect of covariates related to the individual and to the health services on mortality from all causes. Results Age above 60 years, admission to a hospital with emergency services, HIV-associated TB, and readmission to an outpatient facility after disease relapse or loss to follow-up were identified as risk factors for death. Variables related to process and results indicators of Brazil's National TB Program were not associated with mortality from all causes. Conclusions Advanced age, previous treatment for TB, and treatment at a secondary-level outpatient facility or a hospital with emergency services on site were associated with mortality in TB patients. Better strategies to improve TB care delivered at health units are needed to prevent death from TB, especially among the elderly.

RESUMEN Objetivo Identificar los factores individuales y los factores relacionados con los servicios de salud asociados con la muerte de personas con diagnóstico de tuberculosis. Métodos Se realizó un estudio de cohortes no concurrentes con seguimiento pasivo, con un método de nexo probabilístico, para analizar una muestra de pacientes a quienes se les diagnosticó tuberculosis y se notificaron sus casos en el 2006, y se les dio seguimiento hasta el 2008. Se incluyeron casos nuevos, casos con tratamiento anterior (reingreso después de haber abandonado el seguimiento o por recaída) y transferencias entre distintos servicios de salud. Se usaron modelos de riesgos proporcionales para calcular el efecto independiente de las covariables relacionadas con los individuos y con los servicios de salud en la mortalidad por todas las causas. Resultados Se determinó que los factores de riesgo de muerte son: edad mayor de 60 años, ingreso a un hospital con servicios de urgencia, tuberculosis asociada con la infección por el VIH y reingreso a un establecimiento de atención ambulatoria después de la recaída de la enfermedad o de abandonar el seguimiento. Las variables relacionadas con los procesos y los indicadores de resultados del Programa Nacional contra la Tuberculosis de Brasil no se asociaron con la mortalidad por todas las causas. Conclusiones La edad avanzada, el antecedente de tratamiento antituberculoso y el tratamiento en un establecimiento ambulatorio de nivel secundario o un hospital con servicios integrados de urgencia se asociaron con la mortalidad de los pacientes con tuberculosis. Se necesitan mejores estrategias para optimizar los servicios de atención de la tuberculosis que prestan las unidades de salud a fin de evitar la muerte por esta enfermedad, especialmente en las personas de mayor edad.

RESUMO Objetivo Identificar fatores individuais e relacionados aos serviços de saúde associados com mortalidade em indivíduos com diagnóstico de tuberculose (TB). Métodos Estudo longitudinal não concorrente de seguimento passivo por método de linkage probabilístico, realizado em uma amostra de pacientes diagnosticados e notificados com TB em 2006 e seguidos até 2008. Casos novos, com histórico de tratamento anterior (readmitidos após perda de seguimento ou recorrência) ou transmitidos entre diferentes serviços de saúde foram incluídos. Modelos de riscos proporcionais foram utilizados para estimar o efeito independente de covariáveis do indivíduo e do serviço de saúde na mortalidade por todas as causas. Resultados Idade maior de 60 anos, admissão em hospital com serviço de emergência, coinfecção HIV/TB e reingresso a um serviço ambulatorial após recorrência da TB ou perda de seguimento foram identificados como fatores de risco para a morte. Variáveis de processo e indicadores de resultados do Programa Nacional de Controle da Tuberculose não guardaram relação com a mortalidade por todas as causas. Conclusões Idade avançada, tratamento prévio da TB e tratamento em unidade ambulatorial de nível secundário ou em hospital com serviço de emergência no local apresentaram associação com mortalidade em pacientes com TB. São necessárias estratégias melhores para aprimorar a atenção à TB ofertada nas unidades de saúde, principalmente para idosos.

Regular and moderate exercise before experimental sepsis reduces the risk of lung and distal organ injury.

Physical activity modulates inflammation and immune response in both normal and pathologic conditions. We investigated whether regular and moderate exercise before the induction of experimental sepsis reduces the risk of lung and distal organ injury and survival. One hundred twenty-four BALB/c mice were randomly assigned to two groups: sedentary (S) and trained (T). Animals in T group ran on a motorized treadmill, at moderate intensity, 5% grade, 30 min/day, 3 times a week for 8 wk. Cardiac adaptation to exercise was evaluated using echocardiography. Systolic volume and left ventricular mass were increased in T compared with S group. Both T and S groups were further randomized either to sepsis induced by cecal ligation and puncture surgery (CLP) or sham operation (control). After 24 h, lung mechanics and histology, the degree of cell apoptosis in lung, heart, kidney, liver, and small intestine villi, and interleukin (IL)-6, KC (IL-8 murine functional homolog), IL-1ß, IL-10, and number of cells in bronchoalveolar lavage (BALF) and peritoneal lavage (PLF) fluids as well as plasma were measured. In CLP, T compared with S groups showed: 1) improvement in survival; 2) reduced lung static elastance, alveolar collapse, collagen and elastic fiber content, number of neutrophils in BALF, PLF, and plasma, as well as lung and distal organ cell apoptosis; and 3) increased IL-10 in BALF and plasma, with reduced IL-6, KC, and IL-1ß in PLF. In conclusion, regular and moderate exercise before the induction of sepsis reduced the risk of lung and distal organ damage, thus increasing survival.

Effects of oleanolic acid on pulmonary morphofunctional and biochemical variables in experimental acute lung injury.

We analysed the effects of oleanolic acid (OA) on lung mechanics and histology and its possible mechanisms of action in experimental acute lung injury (ALI). BALB/c mice were randomly divided into Control (saline, ip) and ALI (paraquat, 25 mg/kg, ip) groups. At 1 h, both groups were treated with saline (SAL, 50 µl ip), OA (10 mg/kg ip), or dexamethasone (DEXA, 1 mg/kg ip). At 24 h, lung static elastance, viscoelastic pressure, and alveolar collapse reduced more after OA compared to DEXA administration. Tumour necrosis factor-α, macrophage migration inhibitory factor, interleukin-6, interferon-γ, and transforming growth factor-ß mRNA expressions in lung tissue diminished similarly after OA or DEXA. Conversely, only OA avoided reactive oxygen species generation and yielded a significant decrease in nitrite concentration. OA and DEXA restored the reduced glutathione/oxidized glutathione ratio and catalase activity while increasing glutathione peroxidase induced by paraquat. In conclusion, OA improved lung morphofunction by modulating the release of inflammatory mediators and oxidative stress.

Early and late effects of bone marrow-derived mononuclear cell therapy on lung and distal organs in experimental sepsis.

We tested the hypothesis that bone marrow-derived mononuclear cells (BMDMCs) at an early phase of cecal ligation and puncture (CLP)-induced sepsis may have lasting effects on: (1) lung mechanics and histology, (2) the structural remodelling of lung parenchyma, (3) lung, kidney, and liver cell apoptosis, and (4) pro- and anti-inflammatory cytokines and growth factors. At day 1, BMDMC significantly reduced mortality, as well as caspase-3, interleukin (IL)-6 and IL-1ß, vascular endothelial growth factor, platelet-derived growth factor, hepatocyte growth factor, and transforming growth factor-ß, but increased IL-10 mRNA expression in lung tissue in septic mice contributing to endothelium and epithelium alveolar repair and improvement of lung mechanics. BMDMC also prevented the increase of apoptotic cells in lung, liver, and kidney. At day 7, these early functional and morphological effects were preserved or further improved. In conclusion, in the present model of sepsis, the beneficial effects of early administration of BMDMCs on lung and distal organs were preserved, possibly by paracrine mechanisms.

Assisted ventilation modes reduce the expression of lung inflammatory and fibrogenic mediators in a model of mild acute lung injury.

PURPOSE: The goal of the study was to compare the effects of different assisted ventilation modes with pressure controlled ventilation (PCV) on lung histology, arterial blood gases, inflammatory and fibrogenic mediators in experimental acute lung injury (ALI). METHODS: Paraquat-induced ALI rats were studied. At 24 h, animals were anaesthetised and further randomized as follows (n = 6/group): (1) pressure controlled ventilation mode (PCV) with tidal volume (V (T)) = 6 ml/kg and inspiratory to expiratory ratio (I:E) = 1:2; (2) three assisted ventilation modes: (a) assist-pressure controlled ventilation (APCV1:2) with I:E = 1:2, (b) APCV1:1 with I:E = 1:1; and (c) biphasic positive airway pressure and pressure support ventilation (BiVent + PSV), and (3) spontaneous breathing without PEEP in air. PCV, APCV1:1, and APCV1:2 were set with P (insp) = 10 cmH(2)O and PEEP = 5 cmH(2)O. BiVent + PSV was set with two levels of CPAP [inspiratory pressure (P (High) = 10 cmH(2)O) and positive end-expiratory pressure (P (Low) = 5 cmH(2)O)] and inspiratory/expiratory times: T (High) = 0.3 s and T (Low) = 0.3 s. PSV was set as follows: 2 cmH(2)O above P (High) and 7 cmH(2)O above P (Low). All rats were mechanically ventilated in air and PEEP = 5 cmH(2)O for 1 h. RESULTS: Assisted ventilation modes led to better functional improvement and less lung injury compared to PCV. APCV1:1 and BiVent + PSV presented similar oxygenation levels, which were higher than in APCV1:2. Bivent + PSV led to less alveolar epithelium injury and lower expression of tumour necrosis factor-alpha, interleukin-6, and type III procollagen. CONCLUSIONS: In this experimental ALI model, assisted ventilation modes presented greater beneficial effects on respiratory function and a reduction in lung injury compared to PCV. Among assisted ventilation modes, Bi-Vent + PSV demonstrated better functional results with less lung damage and expression of inflammatory mediators.

Prolonged recruitment manoeuvre improves lung function with less ultrastructural damage in experimental mild acute lung injury.

The effects of prolonged recruitment manoeuvre (PRM) were compared with sustained inflation (SI) in paraquat-induced mild acute lung injury (ALI) in rats. Twenty-four hours after ALI induction, rats were anesthetized and mechanically ventilated with VT=6 ml/kg and positive end-expiratory pressure (PEEP)=5 cmH(2)O for 1h. SI was performed with an instantaneous pressure increase of 40 cmH(2)O that was sustained for 40s, while PRM was done by a step-wise increase in positive inspiratory pressure (PIP) of 15-20-25 cmH(2)O above a PEEP of 15 cm H(2)O (maximal PIP=40 cmH(2)O), with interposed periods of PIP=10 cmH(2)O above a PEEP=15 cmH(2)O. Lung static elastance and the amount of alveolar collapse were more reduced with PRM than SI, yielding improved oxygenation. Additionally, tumour necrosis factor-alpha, interleukin-6, interferon-gamma, and type III procollagen mRNA expressions in lung tissue and lung epithelial cell apoptosis decreased more in PRM. In conclusion, PRM improved lung function, with less damage to alveolar epithelium, resulting in reduced pulmonary injury.

Effects of frequency and inspiratory plateau pressure during recruitment manoeuvres on lung and distal organs in acute lung injury.

PURPOSE: To evaluate the effects of frequency and inspiratory plateau pressure (Pplat) during recruitment manoeuvres (RMs) on lung and distal organs in acute lung injury (ALI). METHODS: We studied paraquat-induced ALI rats. At 24 h, rats were anesthetized and RMs were applied using continuous positive airway pressure (CPAP, 40 cmH(2)O/40 s) or three-different sigh strategies: (a) 180 sighs/h and Pplat = 40 cmH(2)O (S180/40), (b) 10 sighs/h and Pplat = 40 cmH(2)O (S10/40), and (c) 10 sighs/h and Pplat = 20 cmH(2)O (S10/20). RESULTS: S180/40 yielded alveolar hyperinflation and increased lung and kidney epithelial cell apoptosis as well as type III procollagen (PCIII) mRNA expression. S10/40 resulted in a reduction in epithelial cell apoptosis and PCIII expression. Static elastance and alveolar collapse were higher in S10/20 than S10/40. CONCLUSIONS: The reduction in sigh frequency led to a protective effect on lung and distal organs, while the combination with reduced Pplat worsened lung mechanics and histology.

Understanding the mechanisms of glutamine action in critically ill patients

Glutamine (Gln) is an important energy source and has been used as a supplementary energy substrate. Furthermore, Gln is an essential component for numerous metabolic functions, including acid-base homeostasis, gluconeogenesis, nitrogen transport and synthesis of proteins and nucleic acids. Therefore, glutamine plays a significant role in cell homeostasis and organ metabolism. This article aims to review the mechanisms of glutamine action during severe illnesses. In critically ill patients, the increase in mortality was associated with a decreased plasma Gln concentration. During catabolic stress, Gln consumption rate exceeds the supply, and both plasma and skeletal muscle pools of free Gln are severely reduced. The dose and route of Gln administration clearly influence its effectiveness: high-dose parenteral appears to be more beneficial than low-dose enteral administration. Experimental studies reported that Gln may protect cells, tissues, and whole organisms from stress and injury through the following mechanisms: attenuation of NF (nuclear factor)-kB activation, a balance between pro- and anti-inflammatory cytokines, reduction in neutrophil accumulation, improvement in intestinal integrity and immune cell function, and enhanced of heat shock protein expression. In conclusion, high-doses of parenteral Gln (>0.50 g/kg/day) demonstrate a greater potential to benefit in critically ill patients, although Gln pathophysiological mechanisms requires elucidation.

A glutamina (Gln) é uma importante fonte de energia e tem sido usada como substrato energético suplementar. Além disso, a Gln é um componente essencial para numerosas funções metabólicas tais como: homeostase ácido-base, gliconeogênese, transporte de nitrogênio e síntese de proteínas e ácidos nucléicos. Portanto, a glutamina desempenha um papel importante na homeostase celular e no metabolismo dos órgãos. Esse artigo objetiva rever os mecanismos de ação da glutamina na doença grave. Em pacientes criticamente enfermos, o aumento da mortalidade foi associado com uma diminuição de Gln plasmática. Durante o estresse catabólico, o consumo de Gln excede a oferta, e a quantidade de glutamina livre no plasma e músculo esquelético encontra-se reduzida. A dose e via de administração da Gln claramente influencia sua eficácia: alta dose por via parenteral parece ser mais benéfica do que uma dose baixa administrada por via enteral. Estudos experimentais relataram que Gln protege as células, tecidos, e todo o organismo do estresse através dos seguintes mecanismos: atenuação na ativação do fator nuclear (NF)-kB, balanço entre citocinas pró- e anti-inflamatórias, redução no acúmulo de neutrófilos, melhora na integridade intestinal e função mune celular, e aumento da expressão da proteína de choque térmico. Em conclusão, o uso de glutamina em altas doses e por via parenteral (>0,50 g/kg/dia) demonstrou ser benéfica em pacientes criticamente enfermos, embora os mecanismos fisiopatoló-gicos necessitam ser melhor elucidados.